7. Project Summary/Abstract Salivary gland tumors constitute 1-6% of head and neck tumors numbering 3600 new cases per year in the US. Though rare, there are 37 histopathological malignant subtypes and 13 benign subtypes of salivary gland tumors, making it one of the most challenging tumors to diagnose. While surgery is the main modality of treatment, advance unresectable primary, recurrent and metastatic tumors are generally fatal. The rarity of the tumors and multiple histopathological subtypes generated major clinical challenges for the early detection, diagnosis, therapeutic interventions and prognosis of patients with salivary gland tumors. This application addresses the missing gaps in salivary gland tumor research by advancing the basic and translational sciences. Our approach is to perform comprehensive molecular characterization of salivary gland tumors using the most advanced omics technologies coupled with advanced data and bioinformatics analysis to develop tissue-based biomarkers for salivary gland malignancy detection as well as the potential use of salivary biomarkers to screen/risk assess symptomatic patients for salivary gland malignancies. In additional a systems network analysis approach (Weighted-Gene Co-Expression Network Analysis, WGCNA) will be use to examine the derived omics databases to identify pivotal molecular pathways and gene targets for salivary gland malignancy development. Collective these approaches will lead to translational and mechanistic insights for salivary tumor development that can be further translated for clinical applications as well as mechanistic evaluations using rodent models for salivary gland carcinogenesis. Six Specific Aims are in place to test the hypothesis in this application. Aim 1 is to procure fresh frozen malignant and benign parotid gland tissues from the UCLA Head & Neck Oncology Clinic. Aim 2 is to perform comprehensive profiling of parotid gland tumors' transcriptome; microRNA and epigenome using most advanced RNA sequencing and methylomics arrays. Aim 3 will perform statistical and bioinformatics analysis for the omics databases to select candidate biomarkers that can detect parotid gland malignancies. These candidate biomarkers will be pre-validated in Aim 4 in an independent cohort of parotid gland malignant and benign tumors. Aim 5 is to explore the hypothesis that tissue-based dysregulated biomarkers in malignant parotid glands are concordantly dysregulated in saliva of these patients. Finally Aim 6 is a systems network based analysis of the omics databases to identify critical biological pathways and gene targets that are pivotal in the development of parotid gland malignancies. These pathway and targets outcome can be evaluated in future mechanistic studies in salivary gland malignancy development by rodent models or cell lines. Our multidisciplinary research team has the expertise and track record to carry out the proposed molecular characterization of parotid gland tumors as well as expertise to carryout the mechanistic and translational next steps to fully materialize the goals of this RFA.